US20090304791A1 - Solid oral forms of ebastine - Google Patents
Solid oral forms of ebastine Download PDFInfo
- Publication number
- US20090304791A1 US20090304791A1 US12/092,477 US9247706A US2009304791A1 US 20090304791 A1 US20090304791 A1 US 20090304791A1 US 9247706 A US9247706 A US 9247706A US 2009304791 A1 US2009304791 A1 US 2009304791A1
- Authority
- US
- United States
- Prior art keywords
- tablet
- ebastine
- dispersible
- tablet according
- outer layer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- MJJALKDDGIKVBE-UHFFFAOYSA-N ebastine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(=O)CCCN1CCC(OC(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 MJJALKDDGIKVBE-UHFFFAOYSA-N 0.000 title claims abstract description 70
- 229960001971 ebastine Drugs 0.000 title claims abstract description 69
- 239000007787 solid Substances 0.000 title claims abstract description 24
- 239000000203 mixture Substances 0.000 claims abstract description 50
- 239000002736 nonionic surfactant Substances 0.000 claims abstract description 37
- 238000002844 melting Methods 0.000 claims abstract description 14
- 230000008018 melting Effects 0.000 claims abstract description 14
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 40
- 239000011159 matrix material Substances 0.000 claims description 34
- 229920003109 sodium starch glycolate Polymers 0.000 claims description 24
- 229940079832 sodium starch glycolate Drugs 0.000 claims description 24
- 239000008109 sodium starch glycolate Substances 0.000 claims description 24
- 235000019359 magnesium stearate Nutrition 0.000 claims description 21
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 17
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 17
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 17
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 17
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 15
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 13
- 229960000913 crospovidone Drugs 0.000 claims description 12
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 12
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 12
- MQFYRUGXOJAUQK-UHFFFAOYSA-N 2-[2-[2-(2-octadecanoyloxyethoxy)ethoxy]ethoxy]ethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCOCCOCCOCCOC(=O)CCCCCCCCCCCCCCCCC MQFYRUGXOJAUQK-UHFFFAOYSA-N 0.000 claims description 10
- 229920000136 polysorbate Polymers 0.000 claims description 10
- 239000011253 protective coating Substances 0.000 claims description 10
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 9
- 229960001021 lactose monohydrate Drugs 0.000 claims description 9
- 239000007884 disintegrant Substances 0.000 claims description 8
- 239000000314 lubricant Substances 0.000 claims description 7
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 7
- RFVNOJDQRGSOEL-UHFFFAOYSA-N 2-hydroxyethyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCO RFVNOJDQRGSOEL-UHFFFAOYSA-N 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 6
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 5
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 5
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 5
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 5
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 5
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 5
- 229920000642 polymer Polymers 0.000 claims description 5
- 235000019739 Dicalciumphosphate Nutrition 0.000 claims description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 4
- 239000001506 calcium phosphate Substances 0.000 claims description 4
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 claims description 4
- 229940038472 dicalcium phosphate Drugs 0.000 claims description 4
- 229910000390 dicalcium phosphate Inorganic materials 0.000 claims description 4
- 229960001375 lactose Drugs 0.000 claims description 4
- 239000008101 lactose Substances 0.000 claims description 4
- 229950008882 polysorbate Drugs 0.000 claims description 4
- 239000007790 solid phase Substances 0.000 claims description 4
- 150000004683 dihydrates Chemical class 0.000 claims description 3
- 239000006185 dispersion Substances 0.000 abstract description 2
- 239000003826 tablet Substances 0.000 description 39
- 239000004480 active ingredient Substances 0.000 description 13
- 238000000034 method Methods 0.000 description 8
- 239000002245 particle Substances 0.000 description 7
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000006731 degradation reaction Methods 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 5
- 239000000796 flavoring agent Substances 0.000 description 5
- 125000005456 glyceride group Chemical group 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- 239000012736 aqueous medium Substances 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 238000007906 compression Methods 0.000 description 4
- 230000006835 compression Effects 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 238000000227 grinding Methods 0.000 description 4
- 230000002209 hydrophobic effect Effects 0.000 description 4
- 229940124531 pharmaceutical excipient Drugs 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- -1 tablets Chemical compound 0.000 description 4
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 3
- 239000004097 EU approved flavor enhancer Substances 0.000 description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- 230000000181 anti-adherent effect Effects 0.000 description 3
- 239000003911 antiadherent Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 235000013355 food flavoring agent Nutrition 0.000 description 3
- 235000019264 food flavour enhancer Nutrition 0.000 description 3
- 235000003599 food sweetener Nutrition 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- FDCJDKXCCYFOCV-UHFFFAOYSA-N 1-hexadecoxyhexadecane Chemical compound CCCCCCCCCCCCCCCCOCCCCCCCCCCCCCCCC FDCJDKXCCYFOCV-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 229920002675 Polyoxyl Polymers 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 239000013065 commercial product Substances 0.000 description 2
- RBLGLDWTCZMLRW-UHFFFAOYSA-K dicalcium;phosphate;dihydrate Chemical compound O.O.[Ca+2].[Ca+2].[O-]P([O-])([O-])=O RBLGLDWTCZMLRW-UHFFFAOYSA-K 0.000 description 2
- 238000007907 direct compression Methods 0.000 description 2
- 239000007919 dispersible tablet Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 235000019634 flavors Nutrition 0.000 description 2
- 238000001033 granulometry Methods 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 239000003605 opacifier Substances 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 238000007873 sieving Methods 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 229940032147 starch Drugs 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- HLZKNKRTKFSKGZ-UHFFFAOYSA-N tetradecan-1-ol Chemical compound CCCCCCCCCCCCCCO HLZKNKRTKFSKGZ-UHFFFAOYSA-N 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- FLPJVCMIKUWSDR-UHFFFAOYSA-N 2-(4-formylphenoxy)acetamide Chemical compound NC(=O)COC1=CC=C(C=O)C=C1 FLPJVCMIKUWSDR-UHFFFAOYSA-N 0.000 description 1
- 239000004925 Acrylic resin Substances 0.000 description 1
- 229920000178 Acrylic resin Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 229920003134 Eudragit® polymer Polymers 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 235000006679 Mentha X verticillata Nutrition 0.000 description 1
- 235000002899 Mentha suaveolens Nutrition 0.000 description 1
- 235000001636 Mentha x rotundifolia Nutrition 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 235000007265 Myrrhis odorata Nutrition 0.000 description 1
- 240000009023 Myrrhis odorata Species 0.000 description 1
- MHQJUHSHQGQVTM-HNENSFHCSA-N Octadecyl fumarate Chemical compound CCCCCCCCCCCCCCCCCCOC(=O)\C=C/C(O)=O MHQJUHSHQGQVTM-HNENSFHCSA-N 0.000 description 1
- 235000012550 Pimpinella anisum Nutrition 0.000 description 1
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003570 air Substances 0.000 description 1
- 230000003266 anti-allergic effect Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical class [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 229940074979 cetyl palmitate Drugs 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 239000007938 effervescent tablet Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- PXDJXZJSCPSGGI-UHFFFAOYSA-N hexadecanoic acid hexadecyl ester Natural products CCCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCC PXDJXZJSCPSGGI-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 229940043348 myristyl alcohol Drugs 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 229940126409 proton pump inhibitor Drugs 0.000 description 1
- 239000000612 proton pump inhibitor Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- AYGJDUHQRFKLBG-UHFFFAOYSA-M sodium;1,1-dioxo-1,2-benzothiazol-3-olate;dihydrate Chemical compound O.O.[Na+].C1=CC=C2C(=O)[N-]S(=O)(=O)C2=C1 AYGJDUHQRFKLBG-UHFFFAOYSA-M 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 229940071138 stearyl fumarate Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4515—Non condensed piperidines, e.g. piperocaine having a butyrophenone group in position 1, e.g. haloperidol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
Definitions
- the present invention relates to solid oral pharmaceutical forms of ebastine comprising a matrix consisting of a solid dispersion of said active ingredient in nonionic surfactants, such that said forms have good solubility and bioavailability properties and improved stability.
- Ebastine is an antihistaminic and antiallergic compound corresponding to the following formula
- said compound has the drawback of its predominantly hydrophobic character causing a low solubility thereof in water and, consequently, reducing the bioavailability of the drug.
- European patent application EP-A-0575481 proposes aqueous liquid compositions of ebastine and other similar compounds for oral administration, which are free from surfactants and contain polyethylene glycol as a solubilizing agent.
- Spanish patent application ES-A-2107375 describes oral liquid compositions of ebastine containing a mixture of hydroxylated carboxylic acids, nonionic surfactants and medium-chain polyols.
- EP-A-0614362 describes solid oral forms of ebastine, mainly tablets, wherein the ebastine is micronized, such that the particles of the active ingredient have the following size characteristics:
- the particles preferably 90% of the particles have a granulometry smaller than 25 ⁇ m
- Micronization is an additional industrial process requiring the use of complex and high-cost machinery, which makes the active ingredient expensive. Furthermore, having a very high specific surface area in contact with the exterior, the micronized active ingredient is more sensitive to the degradation processes caused by the contact with water, air and pharmaceutical excipients.
- Patent application PCT WO02/45693 describes solid matrices in which an active ingredient is dispersed in a mixture of hydrophobic components, and said matrices are useful for preparing solid oral pharmaceutical forms, particularly tablets. Said document puts forth a very long list of several thousands of active ingredients to which said technique could be applied, and among which ebastine is mentioned as another one without any significance.
- the components of the matrices described in WO02/45693, except the active ingredients, are selected from:
- fatty alcohol for example cetyl alcohol and myristyl alcohol
- triglycerides for example glycerin tristearate
- partial glycerides for example glycerin monostearate,
- fatty acid esters for example cetyl palmitate, and
- Partial glycerides show nonionic surfactant characteristics, but their HLBs (hydrophilic-lipophilic balance) are very low, clearly less than 10, which makes their emulsifying power not suitable for O/W (oil/water) systems, although it is suitable for W/0 (water/oil) systems.
- HLBs hydrophilic-lipophilic balance
- glyceryl monostearate shows a HLB of 2.5.
- matrices described in WO02/45693 are therefore not suitable for obtaining ebastine tablets with a fast rate of dissolution of said hydrophobic active ingredient in an aqueous medium (O/W system), and it is clear for the skilled person that the mere mention of ebastine in said document, among a list of several thousands of active ingredients, has no significance.
- the present invention is a composition comprising a matrix containing a solid ebastine dispersion in nonionic surfactants, which allows obtaining oral forms of ebastine having a good performance as regards solubility and bioavailability, and at the same time showing excellent stability.
- solid oral pharmaceutical forms of ebastine which can be obtained from the mentioned matrix also form part of the invention.
- the ebastine tablets comprising said matrix particularly form part of the invention.
- solid oral pharmaceutical forms of ebastine can be prepared, without need of using micronized ebastine, from a composition comprising a matrix containing ebastine dispersed in solid phase in a certain type of nonionic surfactants.
- the matrices of the invention comprise:
- Ebastine is not limited by the particle size and is preferably in a proportion by weight of between 20% and 75%, more preferably between 30% and 70%.
- the pharmaceutically acceptable nonionic surfactants mainly consist of polyols partially esterified with fatty acids, alkoxylated or non-alkoxylated, and mixtures thereof or mixtures thereof with glycerides or other components, and their description is within the reach of the skilled person in the usual handbooks and reference books on pharmaceutical technology, for example in the Handbook of Pharmaceutical Excipients, Fourth Edition 2003, Ed. Pharmaceutical Press, as well as in very widespread commercial catalogs.
- the selected nonionic surfactants have a HLB of between 10 and 20 and a melting point (drop point or softening point) between 30° C. and 70° C.
- GELUCIRE® 50/13 and 44/14 The following commercially accessible products are preferred as nonionic surfactants: GELUCIRE® 50/13 and 44/14, POLYSORBATE 61 and 65 (TWEEN® 61 and 65), BRIJ® 58 and 76, MYRJ® 59, HODAG® 154-S (PEG 32 distearate) and 602-S (PEG 150 distearate), or mixtures thereof.
- GELUCIRE® 50/13 is especially preferred.
- the matrix preferably contains from 25% to 80% by weight of nonionic surfactants, more preferably from 30% to 70% by weight.
- the matrix is obtained by melting, under stirring, the nonionic surfactant or mixture of nonionic surfactants and ebastine at a temperature between 65° C. and 90° C., preferably between 80° C. and 90° C. Once homogenized, the molten mixture is allowed to cool until a temperature of preferably less than 0° C., and the cooled solid mass is subjected to grinding and subsequent sieving in conventional equipment.
- nonionic surfactant or mixture of nonionic surfactants it is preferred to first heat the nonionic surfactant or mixture of nonionic surfactants until a temperature at which the surfactant is molten and then add ebastine with moderate stirring and continue heating until reaching a temperature between 75° C. and 85° C.
- the mixture can be cooled to a temperature between 0° C. and ⁇ 20° C. before grinding.
- the mass can be first cooled until room temperature (about 20° C.) and a first trituration can be carried out until reaching particles of about 1 cm, which are later cooled to between ⁇ 10° C. and ⁇ 20° C. for 10-12 hours and subsequently subjected to grinding and sieving until reaching the desired particle size.
- a matrix in the form of a powdery or granular solid is thus obtained, from which oral pharmaceutical forms can be obtained by means of mixing with other pharmaceutical excipients and applying conventional Galenic techniques, which oral pharmaceutical forms can mainly consist of granulates, capsules and tablets, for example.
- Said forms have a profile for releasing the active ingredient in an aqueous medium at pH 2.0 that is very similar to that obtained with commercial tablets containing micronized ebastine, even somewhat improved, showing in addition improved stability as regards the degradation of the active ingredient when they are subjected to stability tests under different temperature and relative humidity conditions.
- Tablets are preferred among oral pharmaceutical forms, which tablets can be obtained by mixing and homogenizing the matrices of the invention with suitable excipients, optionally if desired, the components can then be partially or completely granulated, and finally, the compression is carried out in suitable conventional machinery.
- the compression can be carried out on completely or partially granulated mixtures of components, or on the non-granulated components, i.e. by means of the direct compression technique that is well known by the skilled person. Tablets obtained by means of direct compression are preferred.
- an outer layer of protective coating can be applied using also conventional techniques, for example by means of coating or spraying.
- Diluents, disintegrants, lubricants, antiadherents, sweeteners, flavor enhancers, flavoring agents, opacifiers, etc. can be mentioned among the suitable excipients for preparing the tablets containing the matrices of the invention.
- Diluents are excipients facilitating the compression of powdery materials and providing resistance to the tablets.
- Microcrystalline cellulose, lactose, dicalcium phosphate, PVP (polyvinylpyrrolidone), hydroxypropyl cellulose (HPC), pregelatinized starch dry flow starch and mixtures thereof, for example, can be used as suitable diluents.
- Preferred diluents for the purpose of the present invention are microcrystalline cellulose (AVICEL® 102, for example), lactose monohydrate, dicalcium phosphate (anhydrous or dihydrate) and lactose/PVP mixtures (LUDIPRES, for example).
- Disintegrants are excipients causing a quick breaking of the tablet when it is introduced in an aqueous medium, and also a quick disgregation of the granules, such that the active ingredient is quickly released.
- Different types of starch and energetic disintegrants such as crospovidone, croscarmellose sodium, sodium starch glycolate and polymers derived from acrylic acid can be mentioned among the disintegrants.
- Lubricants and antiadherents are excipients reducing tensions between particles and favoring the formation of the tablet, and they also prevent the adhesion of the particles.
- Talc, stearic acid alkaline earth salts, especially magnesium and calcium stearates, stearic acid, PEG 4000 and 6000 and stearyl fumarate can be mentioned among them.
- One of the most used antiadherents is colloidal silica.
- the formulations of this invention can further contain sweeteners, flavoring agents and flavor enhancers for the purpose of achieving suitable organoleptic characteristics (flavor and taste) which are acceptable for patients.
- suitable organoleptic characteristics frlavor and taste
- Sodium saccharin, aspartame, mannitol, xylitol, sucrose, sorbitol and ammonium glycyrrhizinate can be mentioned among the sweeteners and fruit and plant flavors, for example orange, anise, mint, etc. can be mentioned among the flavoring agents and flavor enhancers.
- the coatings available on the market known as OPADRY® usually containing a mixture of hydroxypropylmethylcellulose (HPMC) and polyethylene glycol (MACROGOL), in addition to pigments and opacifiers such as titanium dioxide can be used.
- OPADRY® usually containing a mixture of hydroxypropylmethylcellulose (HPMC) and polyethylene glycol (MACROGOL), in addition to pigments and opacifiers such as titanium dioxide
- HPMC hydroxypropylmethylcellulose
- MACROGOL polyethylene glycol
- Gastrosoluble acrylic resins such as EUDRAGIT® E type resins, can be used.
- dispersible or mouth-dispersible tablets i.e. tablets that dissolve quickly in a glass of water and allow their administration in liquid form to patients for whom it is difficult to swallow whole tablets, or tablets that dissolve in the mouth, are to be obtained
- a suitable selection of the aforementioned energetic disintegrants crospovidone, croscarmellose sodium, sodium starch glycolate and polymers derived from acrylic acid
- crospovidone, croscarmellose sodium, sodium starch glycolate and polymers derived from acrylic acid can be carried out, increasing their proportion by weight to achieve the desired rate of disgregation.
- an alternative consists of preparing effervescent tablets, in which part of the components form an alkaline granulate containing a chemical compound which can generate a gas, preferably sodium bicarbonate, whereas another part consists of an acid granulate, with citric acid for example, such that when it is put in contact with water, the gas (carbon dioxide) causing effervescence and quickly disgregating the tablet is generated.
- a chemical compound which can generate a gas, preferably sodium bicarbonate
- citric acid for example
- the tablets of the invention comprise:
- the tablets preferably comprise at least one diluent excipient selected from microcrystalline cellulose, lactose monohydrate, dicalcium phosphate (anhydrous or dihydrate) and lactose/PVP mixtures, or mixtures thereof.
- the tablets also preferably comprise at least one disintegrant selected from crospovidone, croscarmellose sodium, sodium starch glycolate and polymers derived from acrylic acid.
- the tablets also preferably comprise magnesium stearate as a lubricant.
- Tablets unitarily comprising the following are especially preferred:
- the cooled mass was ground in a mill with a 6 mm opening mesh, and was stored until the time of its use for preparing the pharmaceutical form.
- a matrix containing 57% by weight of ebastine and 43% by weight of GELUCIRE® 50/13 was thus obtained.
- GELUCIRE® 50/13 is a commercial nonionic surfactant consisting of a mixture of glycerides and fatty acid esters with polyethylene glycol, having a HLB of 13 and a melting point between 47° C. and 51° C. (V-shaped capillary tube).
- PEG 150 distearate is a nonionic surfactant which can be acquired on the market, for example with the reference HODAG® 602-S, having a HLB of 18.4 and a melting point between 53° C. and 57° C.
- TWEEN® 65 is a commercial nonionic surfactant formed by fatty acid esters with polyoxyethylenated sorbitan. It has a HLB of 10.5 and a melting point between 53° C. and 57° C.
- MYRJ® 45 is a commercial nonionic surfactant consisting of polyethylene glycol 100 monostearate. It has a HLB of 18.8 and a melting point of about 46° C.
- BRIJ® (58 and 76 are commercial nonionic surfactants.
- BRIJ® 58 is a polyoxyl 20 cetyl ether with a HLB of 15.7 and a melting point of 38° C.
- BRIJ® 76 is a polyoxyl 10 cetyl ether with a HLB of 12.4 and a melting point of 38° C.
- GELUCIRE® 44/14 is a commercial nonionic surfactant similar to GELUCIRE® 50/13, having a HLB of 14 and a melting point between 42° C. and 46° C.
- Tablets having the following composition per tablet were obtained from the matrix of Example 1:
- the tablets were obtained as follows:
- Example 1 The matrix obtained in Example 1 and AVICEL® 102 were mixed and sieved by means of an oscillating granulator-sieve provided with a 0.8 mm mesh. The mixture was stirred for 5 minutes and then sodium starch glycolate was added over 10 minutes. Magnesium stearate was then added and it was mixed for 1 more minute.
- the mixture thus obtained was compressed in a rotary compression machine provided with biconvex and smooth punches with a diameter of 9 mm.
- the tablets according to the invention show dissolution profiles that are similar to that of the tablets of the prior state of the art containing micronized ebastine, being even somewhat better as regards the quickness of dissolution.
- a batch of the tablets obtained according to that described in this example and a batch of tablets of the commercial product EBASTEL® FORTE were subjected to stability tests in different temperature and relative humidity conditions.
- the degradation level over time was determined by means of the total impurity content, referred to ebastine, analyzed by means of HPLC techniques.
- Example 17 EBASTEL ® FORTE (% of total (% of total impurities with impurities with Conditions Time respect to ebastine) respect to ebastine) 25° C. Start 0.07 0.22 60% RH 3 months 0.12 0.47 6 months 0.07 0.64 30° C. Start 0.07 0.22 65% RH 3 months 0.06 0.56 6 months 0.04 0.77 40° C. Start 0.07 0.22 75% RH 3 months 0.06 0.57 6 months 0.06 0.60
- the ebastine contained in the tablets of the invention remains stable over time, without undergoing degradations, and the total impurity content does not increase.
- ebastine undergoes a progressive increase in the total impurity content, which indicates greater degradation and less stability.
- the tablets of Examples 18 to 32 show good solubility properties and also good stability.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Zoology (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to compositions in the form of matrices consisting of solid ebastine dispersions in nonionic surfactants having a HLB of between 10 and 20 and a melting point of between 30° C. and 70° C. The invention also relates to solid oral pharmaceutical forms of ebastine containing said matrices, particularly tablets, and having good solubility and bioavailability properties and improved stability.
Description
- This application is a U.S. National Phase application of PCT Application No. PCT/ES2006/000581, filed Oct. 20, 2006.
- The present invention relates to solid oral pharmaceutical forms of ebastine comprising a matrix consisting of a solid dispersion of said active ingredient in nonionic surfactants, such that said forms have good solubility and bioavailability properties and improved stability.
- Ebastine is an antihistaminic and antiallergic compound corresponding to the following formula
- and was described in European patent application EP-A-0134124.
- For the preparation of pharmaceutical forms for oral administration, said compound has the drawback of its predominantly hydrophobic character causing a low solubility thereof in water and, consequently, reducing the bioavailability of the drug.
- European patent application EP-A-0575481 proposes aqueous liquid compositions of ebastine and other similar compounds for oral administration, which are free from surfactants and contain polyethylene glycol as a solubilizing agent.
- Spanish patent application ES-A-2107375 describes oral liquid compositions of ebastine containing a mixture of hydroxylated carboxylic acids, nonionic surfactants and medium-chain polyols.
- European patent application EP-A-0614362 describes solid oral forms of ebastine, mainly tablets, wherein the ebastine is micronized, such that the particles of the active ingredient have the following size characteristics:
- maximum size smaller than 200 μm,
- average granulometry between 0.5 and 15 μm,
- preferably 90% of the particles have a granulometry smaller than 25 μm,
- and this makes the solid oral forms have an initial rate of dissolution greater than that obtained if ebastine is not micronized.
- Micronization is an additional industrial process requiring the use of complex and high-cost machinery, which makes the active ingredient expensive. Furthermore, having a very high specific surface area in contact with the exterior, the micronized active ingredient is more sensitive to the degradation processes caused by the contact with water, air and pharmaceutical excipients.
- It is therefore still necessary to have alternative solid oral forms of ebastine which do not have the mentioned drawbacks.
- Patent application PCT WO02/45693 describes solid matrices in which an active ingredient is dispersed in a mixture of hydrophobic components, and said matrices are useful for preparing solid oral pharmaceutical forms, particularly tablets. Said document puts forth a very long list of several thousands of active ingredients to which said technique could be applied, and among which ebastine is mentioned as another one without any significance.
- Actually, the skilled person who reads the mentioned document easily understands that the problem intended to be solved is improving the stability of certain known active ingredients as proton pump inhibitors (PPI).
- The components of the matrices described in WO02/45693, except the active ingredients, are selected from:
- fatty alcohol, for example cetyl alcohol and myristyl alcohol
- triglycerides, for example glycerin tristearate,
- partial glycerides, for example glycerin monostearate,
- fatty acid esters, for example cetyl palmitate, and
- furthermore, optionally but preferably, a solid paraffin.
- All of them are clearly hydrophobic components, and except in the case of partial glycerides, none of them can be considered to be a surfactant.
- Partial glycerides show nonionic surfactant characteristics, but their HLBs (hydrophilic-lipophilic balance) are very low, clearly less than 10, which makes their emulsifying power not suitable for O/W (oil/water) systems, although it is suitable for W/0 (water/oil) systems. For example, glyceryl monostearate shows a HLB of 2.5.
- The matrices described in WO02/45693 are therefore not suitable for obtaining ebastine tablets with a fast rate of dissolution of said hydrophobic active ingredient in an aqueous medium (O/W system), and it is clear for the skilled person that the mere mention of ebastine in said document, among a list of several thousands of active ingredients, has no significance.
- The present invention is a composition comprising a matrix containing a solid ebastine dispersion in nonionic surfactants, which allows obtaining oral forms of ebastine having a good performance as regards solubility and bioavailability, and at the same time showing excellent stability.
- The solid oral pharmaceutical forms of ebastine which can be obtained from the mentioned matrix also form part of the invention.
- The ebastine tablets comprising said matrix particularly form part of the invention.
- The authors of the present invention have discovered that solid oral pharmaceutical forms of ebastine can be prepared, without need of using micronized ebastine, from a composition comprising a matrix containing ebastine dispersed in solid phase in a certain type of nonionic surfactants.
- The matrices of the invention comprise:
-
- (i) from 10% to 90% by weight of ebastine, and
- (ii) from 10% to 90% by weight of one or more pharmaceutically acceptable nonionic surfactants having a HLB (hydrophilic-lipophilic balance) of between 10 and 20 and a melting point between 30° C. and 70° C.,
wherein ebastine is dispersed, in a solid phase, in the nonionic surfactant.
- Ebastine is not limited by the particle size and is preferably in a proportion by weight of between 20% and 75%, more preferably between 30% and 70%.
- The pharmaceutically acceptable nonionic surfactants mainly consist of polyols partially esterified with fatty acids, alkoxylated or non-alkoxylated, and mixtures thereof or mixtures thereof with glycerides or other components, and their description is within the reach of the skilled person in the usual handbooks and reference books on pharmaceutical technology, for example in the Handbook of Pharmaceutical Excipients, Fourth Edition 2003, Ed. Pharmaceutical Press, as well as in very widespread commercial catalogs.
- As has already been indicated, for the purposes of the present invention, it is important that the selected nonionic surfactants have a HLB of between 10 and 20 and a melting point (drop point or softening point) between 30° C. and 70° C.
- The following commercially accessible products are preferred as nonionic surfactants: GELUCIRE® 50/13 and 44/14, POLYSORBATE 61 and 65 (TWEEN® 61 and 65), BRIJ® 58 and 76, MYRJ® 59, HODAG® 154-S (PEG 32 distearate) and 602-S (PEG 150 distearate), or mixtures thereof. GELUCIRE® 50/13 is especially preferred.
- The matrix preferably contains from 25% to 80% by weight of nonionic surfactants, more preferably from 30% to 70% by weight.
- The matrix is obtained by melting, under stirring, the nonionic surfactant or mixture of nonionic surfactants and ebastine at a temperature between 65° C. and 90° C., preferably between 80° C. and 90° C. Once homogenized, the molten mixture is allowed to cool until a temperature of preferably less than 0° C., and the cooled solid mass is subjected to grinding and subsequent sieving in conventional equipment.
- It is preferred to first heat the nonionic surfactant or mixture of nonionic surfactants until a temperature at which the surfactant is molten and then add ebastine with moderate stirring and continue heating until reaching a temperature between 75° C. and 85° C.
- It is convenient to cool the mixture until a temperature that is low enough to allow a correct and effective grinding. For example, the mixture can be cooled to a temperature between 0° C. and −20° C. before grinding.
- If desired, the mass can be first cooled until room temperature (about 20° C.) and a first trituration can be carried out until reaching particles of about 1 cm, which are later cooled to between −10° C. and −20° C. for 10-12 hours and subsequently subjected to grinding and sieving until reaching the desired particle size.
- A matrix in the form of a powdery or granular solid is thus obtained, from which oral pharmaceutical forms can be obtained by means of mixing with other pharmaceutical excipients and applying conventional Galenic techniques, which oral pharmaceutical forms can mainly consist of granulates, capsules and tablets, for example.
- Said forms have a profile for releasing the active ingredient in an aqueous medium at pH 2.0 that is very similar to that obtained with commercial tablets containing micronized ebastine, even somewhat improved, showing in addition improved stability as regards the degradation of the active ingredient when they are subjected to stability tests under different temperature and relative humidity conditions.
- The selection of the additional excipients is not critical and will depend on the selected pharmaceutical form and on the Galenic technique to be used. All of this only represents routine work for the skilled person, taking into account his common general knowledge and the usual handbooks and reference books in pharmaceutical technology such as, among others, the aforementioned Handbook of Pharmaceutical excipients, Remington (The Science and Practice of Pharmacy), 20th Ed., etc.
- Tablets are preferred among oral pharmaceutical forms, which tablets can be obtained by mixing and homogenizing the matrices of the invention with suitable excipients, optionally if desired, the components can then be partially or completely granulated, and finally, the compression is carried out in suitable conventional machinery.
- In the event that steps of completely or partially granulating the components are included, it is preferable for said granulation to be carried out in dry conditions.
- The compression can be carried out on completely or partially granulated mixtures of components, or on the non-granulated components, i.e. by means of the direct compression technique that is well known by the skilled person. Tablets obtained by means of direct compression are preferred.
- Once the tablet has been obtained, if desired, an outer layer of protective coating can be applied using also conventional techniques, for example by means of coating or spraying.
- Diluents, disintegrants, lubricants, antiadherents, sweeteners, flavor enhancers, flavoring agents, opacifiers, etc. can be mentioned among the suitable excipients for preparing the tablets containing the matrices of the invention.
- Diluents are excipients facilitating the compression of powdery materials and providing resistance to the tablets. Microcrystalline cellulose, lactose, dicalcium phosphate, PVP (polyvinylpyrrolidone), hydroxypropyl cellulose (HPC), pregelatinized starch dry flow starch and mixtures thereof, for example, can be used as suitable diluents. Preferred diluents for the purpose of the present invention are microcrystalline cellulose (AVICEL® 102, for example), lactose monohydrate, dicalcium phosphate (anhydrous or dihydrate) and lactose/PVP mixtures (LUDIPRES, for example).
- Disintegrants are excipients causing a quick breaking of the tablet when it is introduced in an aqueous medium, and also a quick disgregation of the granules, such that the active ingredient is quickly released. Different types of starch and energetic disintegrants, such as crospovidone, croscarmellose sodium, sodium starch glycolate and polymers derived from acrylic acid can be mentioned among the disintegrants.
- Lubricants and antiadherents are excipients reducing tensions between particles and favoring the formation of the tablet, and they also prevent the adhesion of the particles. Talc, stearic acid alkaline earth salts, especially magnesium and calcium stearates, stearic acid, PEG 4000 and 6000 and stearyl fumarate can be mentioned among them. One of the most used antiadherents is colloidal silica.
- The formulations of this invention can further contain sweeteners, flavoring agents and flavor enhancers for the purpose of achieving suitable organoleptic characteristics (flavor and taste) which are acceptable for patients. Sodium saccharin, aspartame, mannitol, xylitol, sucrose, sorbitol and ammonium glycyrrhizinate can be mentioned among the sweeteners and fruit and plant flavors, for example orange, anise, mint, etc. can be mentioned among the flavoring agents and flavor enhancers.
- In the event that the tablets are provided with an outer coating, the coatings available on the market known as OPADRY®, usually containing a mixture of hydroxypropylmethylcellulose (HPMC) and polyethylene glycol (MACROGOL), in addition to pigments and opacifiers such as titanium dioxide can be used. Gastrosoluble acrylic resins, such as EUDRAGIT® E type resins, can be used.
- When dispersible or mouth-dispersible tablets, i.e. tablets that dissolve quickly in a glass of water and allow their administration in liquid form to patients for whom it is difficult to swallow whole tablets, or tablets that dissolve in the mouth, are to be obtained, a suitable selection of the aforementioned energetic disintegrants (crospovidone, croscarmellose sodium, sodium starch glycolate and polymers derived from acrylic acid) can be carried out, increasing their proportion by weight to achieve the desired rate of disgregation.
- To obtain dispersible tablets, an alternative consists of preparing effervescent tablets, in which part of the components form an alkaline granulate containing a chemical compound which can generate a gas, preferably sodium bicarbonate, whereas another part consists of an acid granulate, with citric acid for example, such that when it is put in contact with water, the gas (carbon dioxide) causing effervescence and quickly disgregating the tablet is generated.
- The tablets of the invention comprise:
-
- (a) An amount of the matrix containing ebastine dispersed in solid phase in nonionic surfactants, which is enough to provide an effective unit dose of ebastine,
- (b) At least one pharmaceutically acceptable excipient.
- The tablets preferably comprise at least one diluent excipient selected from microcrystalline cellulose, lactose monohydrate, dicalcium phosphate (anhydrous or dihydrate) and lactose/PVP mixtures, or mixtures thereof.
- The tablets also preferably comprise at least one disintegrant selected from crospovidone, croscarmellose sodium, sodium starch glycolate and polymers derived from acrylic acid.
- The tablets also preferably comprise magnesium stearate as a lubricant.
- Tablets unitarily comprising the following are especially preferred:
-
- (a) from 30 to 50 mg of a solid matrix containing between 30% and 70% by weight of ebastine dispersed in a nonionic surfactant or mixture of nonionic surfactants, having a HLB of between 10 and 20 and a melting point between 30° C. and 70° C.,
- (b) from 150 to 300 mg of microcrystalline cellulose,
- (c) from 2 to 7 mg of sodium starch glycolate, and
- (d) from 0.5 to 1.5 mg of magnesium stearate.
- The following examples are set forth below for the purposes of sufficiently completing the previous description:
- 15.0 g of GELUCIRE® 50/13 were heated at 70° C. until it had melted completely and then 20.0 g of ebastine were incorporated, with moderate stirring, and it was heated until 85° C. Once all the mass had melted and had a homogeneous appearance, it was poured in a siliconized tray, such that the mass formed a layer with a thickness of 0.5 cm, and the tray was then introduced in the refrigerator at −15° C. for 10 to 12 hours.
- The cooled mass was ground in a mill with a 6 mm opening mesh, and was stored until the time of its use for preparing the pharmaceutical form. A matrix containing 57% by weight of ebastine and 43% by weight of GELUCIRE® 50/13 was thus obtained.
- GELUCIRE® 50/13 is a commercial nonionic surfactant consisting of a mixture of glycerides and fatty acid esters with polyethylene glycol, having a HLB of 13 and a melting point between 47° C. and 51° C. (V-shaped capillary tube).
- The matrices of ebastine shown in table 1 below were obtained in a manner similar to that described in Example 1.
-
TABLE 1 Example Ebastine Nonionic surfactant (Matrix) (% by weight) (% by weight and identification) 2 57% 43% of PEG 150 distearate 3 57% 43% of TWEEN ® 65 4 57% 43% of MYRJ ® 45 5 57% 43% of BRIJ ® 58 6 57% 43% of BRIJ ® 76 7 25% 75% of GELUCIRE ® 44/14 8 50% 50% of GELUCIRE ® 44/14 9 33% 67% of GELUCIRE ® 44/14 10 40% 60% of GELUCIRE ® 44/14 11 63% 37% of GELUCIRE ® 44/14 12 33% 67% of GELUCIRE ® 50/13 13 40% 60% of GELUCIRE ® 50/13 14 50% 50% of GELUCIRE ® 50/13 15 67% 33% of GELUCIRE ® 50/13 16 61.5% 38.5% of GELUCIRE ® 50/13 - PEG 150 distearate is a nonionic surfactant which can be acquired on the market, for example with the reference HODAG® 602-S, having a HLB of 18.4 and a melting point between 53° C. and 57° C.
- TWEEN® 65 is a commercial nonionic surfactant formed by fatty acid esters with polyoxyethylenated sorbitan. It has a HLB of 10.5 and a melting point between 53° C. and 57° C.
- MYRJ® 45 is a commercial nonionic surfactant consisting of polyethylene glycol 100 monostearate. It has a HLB of 18.8 and a melting point of about 46° C.
- BRIJ® (58 and 76 are commercial nonionic surfactants. BRIJ® 58 is a polyoxyl 20 cetyl ether with a HLB of 15.7 and a melting point of 38° C. BRIJ® 76 is a polyoxyl 10 cetyl ether with a HLB of 12.4 and a melting point of 38° C.
- GELUCIRE® 44/14 is a commercial nonionic surfactant similar to GELUCIRE® 50/13, having a HLB of 14 and a melting point between 42° C. and 46° C.
- Tablets having the following composition per tablet were obtained from the matrix of Example 1:
-
Matrix (57% ebastine and 43% GELUCIRE ® 50/13) 35.0 mg AVICEL ® 102 (microcrystalline cellulose) 219.5 mg Sodium starch glycolate 4.5 mg Magnesium stearate 1.0 mg - The tablets were obtained as follows:
- The matrix obtained in Example 1 and AVICEL® 102 were mixed and sieved by means of an oscillating granulator-sieve provided with a 0.8 mm mesh. The mixture was stirred for 5 minutes and then sodium starch glycolate was added over 10 minutes. Magnesium stearate was then added and it was mixed for 1 more minute.
- The mixture thus obtained was compressed in a rotary compression machine provided with biconvex and smooth punches with a diameter of 9 mm.
- Two batches of tablets, A and B, with the same composition and manufactured independently according to the described method, were subjected to an in vitro dissolution profile test in aqueous medium at pH 2.0. A batch of tablets of the commercial product EBASTEL® FORTE, containing micronized ebastine, was also subjected to said test in the same conditions.
- The ebastine content in solution was analyzed over time and the result shown in Table 2 below were obtained:
-
TABLE 2 Batch A Batch B EBASTEL ® FORTE Time (ebastine in (ebastine in (ebastine in (minutes) solution in %) solution in %) solution in %) 5 88.6 76.4 78.9 10 96.3 94.4 88.0 15 98.4 97.4 91.2 20 99.3 99.1 93.0 30 100.0 99.5 94.1 45 100.8 100.5 95.2 60 101.2 100.8 95.8 - As observed, taking into account the typical errors of the method, it can be affirmed that the tablets according to the invention show dissolution profiles that are similar to that of the tablets of the prior state of the art containing micronized ebastine, being even somewhat better as regards the quickness of dissolution.
- A batch of the tablets obtained according to that described in this example and a batch of tablets of the commercial product EBASTEL® FORTE were subjected to stability tests in different temperature and relative humidity conditions. The degradation level over time was determined by means of the total impurity content, referred to ebastine, analyzed by means of HPLC techniques.
- The results are set forth in Table 3 below:
-
TABLE 3 Example 17 EBASTEL ® FORTE (% of total (% of total impurities with impurities with Conditions Time respect to ebastine) respect to ebastine) 25° C. Start 0.07 0.22 60% RH 3 months 0.12 0.47 6 months 0.07 0.64 30° C. Start 0.07 0.22 65% RH 3 months 0.06 0.56 6 months 0.04 0.77 40° C. Start 0.07 0.22 75% RH 3 months 0.06 0.57 6 months 0.06 0.60 - As observed in Table 3, in the different tested conditions, the ebastine contained in the tablets of the invention remains stable over time, without undergoing degradations, and the total impurity content does not increase. On the contrary, in the tablets of the state of the art, ebastine undergoes a progressive increase in the total impurity content, which indicates greater degradation and less stability.
- By following methods similar to that described in Example 17, ebastine tablets the composition of which is shown below are prepared from the matrices of ebastine of Examples 2 to 16:
-
-
Matrix of Example 2 35.0 mg AVICEL ® 102 (microcrystalline cellulose) 219.5 mg Sodium starch glycolate 4.5 mg Magnesium stearate 1.0 mg -
-
Matrix of Example 3 35.0 mg AVICEL ® 102 (microcrystalline cellulose) 219.5 mg Sodium starch glycolate 4.5 mg Magnesium stearate 1.0 mg -
-
Matrix of Example 4 35.0 mg AVICEL ® 102 (microcrystalline cellulose) 219.5 mg Sodium starch glycolate 4.5 mg Magnesium stearate 1.0 mg -
-
Matrix of Example 5 35.0 mg AVICEL ® 102 (microcrystalline cellulose) 219.5 mg Sodium starch glycolate 4.5 mg Magnesium stearate 1.0 mg -
-
Matrix of Example 6 35.0 mg AVICEL ® 102 (microcrystalline cellulose) 219.5 mg Sodium starch glycolate 4.5 mg Magnesium stearate 1.0 mg -
-
Matrix of Example 7 40.0 mg Lactose monohydrate (GRANULAC ® 200) 64.0 mg PVP (PVPK 25) 20.0 mg Sodium starch glycolate 6.0 mg -
-
Matrix of Example 8 20.0 mg Lactose monohydrate (GRANULAC ® 200) 99.5 mg Sodium starch glycolate 10.0 mg Magnesium stearate 0.5 mg -
-
Matrix of Example 9 30.0 mg Dicalcium phosphate dihydrate 82.5 mg Crospovidone 6.5 mg Sodium starch glycolate 10.5 mg Magnesium stearate 0.5 mg -
-
Matrix of Example 10 25.0 mg Lactose monohydrate (GRANULAC ® 200) 30.0 mg Lactose monohydrate (Fast flo) 194.8 mg Crospovidone 46.2 mg Sodium starch glycolate 33.0 mg Magnesium stearate 1.0 mg -
-
Matrix of Example 11 16.0 mg Lactose monohydrate (GRANULAC ® 200) 10.0 mg Lactose monohydrate (Fast flo) 68.3 mg PVP (PVPK 25) 20.0 mg Sodium starch glycolate 13.0 mg Magnesium stearate 0.7 mg -
-
Matrix of Example 12 60.0 mg AVICEL ® 102 (microcrystalline cellulose) 123.6 mg Sodium starch glycolate 26.0 mg Crospovidone 40.0 mg Sodium lauryl sulfate 10.4 mg -
-
Matrix of Example 13 50.0 mg AVICEL ® 102 (microcrystalline cellulose) 133.6 mg Sodium starch glycolate 26.0 mg Crospovidone 40.0 mg Sodium lauryl sulfate 10.4 mg -
-
Matrix of Example 14 40.0 mg AVICEL ® 102 (microcrystalline cellulose) 143.6 mg Sodium starch glycolate 26.0 mg Crospovidone 40.0 mg Sodium lauryl sulfate 10.4 mg -
-
Matrix of Example 15 30.0 mg AVICEL ® 102 (microcrystalline cellulose) 162.7 mg Sodium starch glycolate 26.0 mg Crospovidone 40.0 mg Magnesium stearate 1.3 mg -
-
Matrix of Example 16 32.5 mg AVICEL ® 102 (microcrystalline cellulose) 160.2 mg Sodium starch glycolate 26.0 mg Crospovidone 40.0 mg Magnesium stearate 1.3 mg - The tablets of Examples 18 to 32 show good solubility properties and also good stability.
- Although the invention is illustrated and described herein with reference to specific embodiments, the invention is not intended to be limited to the details shown. Rather, various modifications may be made in the details within the scope and range of equivalents of the claims and without departing from the invention.
Claims (40)
1. A composition useful for preparing solid oral pharmaceutical forms of ebastine, said composition being in the form of a matrix comprising:
(i) from 10% to 90% by weight of ebastine, and
(ii) from 10% to 90% by weight of one or more pharmaceutically acceptable nonionic surfactants having a HLB (hydrophilic-lipophilic balance) of between 10 and 20 and a melting point between 30° C. and 70° C.,
wherein ebastine is dispersed, in a solid phase, in the nonionic surfactant.
2. A composition according to claim 1 , wherein the ebastine is between 20% and 75% by weight and the nonionic surfactant is between 25% to 80% by weight.
3. A composition according to claim 2 , wherein the ebastine is between 30% and 70% by weight and the nonionic surfactant is between 30% to 70% by weight.
4. A composition according to claim 1 , wherein the nonionic surfactant is selected from the group consisting of the commercial products GELUCIRE® 50/13 and 44/14, POLYSORBATE 61 and 65 (TWEEN® 61 and 65), BRIJ® 58 and 76, MYRJ® 59, HODAG® 154-S (PEG 32 distearate) and 602-S (PEG 150 distearate), and mixtures thereof.
5. A composition according to claim 4 , wherein the nonionic surfactant is GELUCIRE® 50/13.
6. A solid pharmaceutical form of ebastine for oral administration comprising the compositions of claim 1 and at least one pharmaceutically acceptable excipient.
7. An ebastine tablet comprising:
(a) an amount of the compositions of claim 1 which is enough to provide an effective unit dose of ebastine, and
(b) at least one pharmaceutically acceptable excipient.
8. A tablet according to claim 7 , comprising at least one diluent excipient selected from the group consisting of microcrystalline cellulose, lactose monohydrate, dicalcium phosphate (anhydrous or dihydrate) and lactose/PVP mixtures, or mixtures thereof.
9. A tablet according to claim 7 , comprising at least one disintegrant selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate and polymers derived from acrylic acid.
10. A tablet according to claim 7 , comprising magnesium stearate as a lubricant.
11. A tablet comprising:
(a) from 30 to 50 mg of a solid matrix containing between 30% and 70% by weight of ebastine dispersed in a nonionic surfactant or mixture of nonionic surfactants, having a HLB between 10 and 20 and a melting point between 30° C. and 70° C.,
(b) from 150 to 300 mg of microcrystalline cellulose,
(c) from 2 to 7 mg of sodium starch glycolate, and
(d) from 0.5 to 1.5 mg of magnesium stearate.
12. A tablet according to claim 7 , further comprising an outer layer of protective coating.
13. A tablet according to claim 7 , wherein the tablet is a dispersible or mouth-dispersible type tablet.
14. The use of the compositions of claim 1 for preparing solid pharmaceutical forms of ebastine for oral administration.
15. The use according to claim 14 , wherein the pharmaceutical form is a tablet.
16. A composition according to claim 2 , wherein the nonionic surfactant is selected from the group consisting of the commercial products GELUCIRE® 50/13 and 44/14, POLYSORBATE 61 and 65 (TWEEN® 61 and 65), BRIJ® 58 and 76, MYRJ® 59, HODAG® 154-S (PEG 32 distearate) and 602-S (PEG 150 distearate), and mixtures thereof.
17. A composition according to claim 3 , wherein the nonionic surfactant is selected from the group consisting of the commercial products GELUCIRE® 50/13 and 44/14, POLYSORBATE 61 and 65 (TWEEN® 61 and 65), BRIJ® 58 and 76, MYRJ® 59, HODAG® 154-S (PEG 32 distearate) and 602-S (PEG 150 distearate), and mixtures thereof.
18. A tablet according to claim 8 , further comprising at least one disintegrant selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate and polymers derived from acrylic acid.
19. A tablet according to claim 8 , further comprising an outer layer of protective coating.
20. A tablet according to claim 9 , further comprising an outer layer of protective coating.
21. A tablet according to claim 10 , further comprising an outer layer of protective coating.
22. A tablet according to claim 11 , further comprising an outer layer of protective coating.
23. A tablet according to claim 8 , wherein the tablet is a dispersible or mouth-dispersible type tablet.
24. A tablet according to claim 9 , wherein the tablet is a dispersible or mouth-dispersible type tablet.
25. A tablet according to claim 10 , wherein the tablet is a dispersible or mouth-dispersible type tablet.
26. A tablet according to claim 11 , wherein the tablet is a dispersible or mouth-dispersible type tablet.
27. A tablet according to claim 12 , wherein the tablet is a dispersible or mouth-dispersible type tablet.
28. The use of the compositions of claim 2 for preparing solid pharmaceutical forms of ebastine for oral administration.
29. The use of the compositions of claim 3 for preparing solid pharmaceutical forms of ebastine for oral administration.
30. The use of the compositions of claim 4 for preparing solid pharmaceutical forms of ebastine for oral administration.
31. The use of the compositions of claim 5 for preparing solid pharmaceutical forms of ebastine for oral administration.
32. A tablet according to claim 18 , further comprising magnesium stearate as a lubricant.
33. A tablet according to claim 8 , further comprising magnesium stearate as a lubricant.
34. A tablet according to claim 9 , further comprising magnesium stearate as a lubricant.
35. A tablet according to claim 18 , further comprising an outer layer of protective coating.
36. A tablet according to claim 32 , further comprising an outer layer of protective coating.
37. A tablet according to claim 33 , further comprising an outer layer of protective coating.
38. A tablet according to claim 34 , further comprising an outer layer of protective coating.
39. A tablet according to claim 18 , wherein the tablet is a dispersible or mouth-dispersible type tablet.
40. A tablet according to claim 35 , wherein the tablet is a dispersible or mouth-dispersible type tablet.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ES200502686A ES2277767B1 (en) | 2005-11-04 | 2005-11-04 | SOLID ORAL FORMS OF EBASTINA. |
ESP200502686 | 2005-11-04 | ||
PCT/ES2006/000581 WO2007051877A1 (en) | 2005-11-04 | 2006-10-20 | Solid oral forms of ebastine |
Publications (1)
Publication Number | Publication Date |
---|---|
US20090304791A1 true US20090304791A1 (en) | 2009-12-10 |
Family
ID=38005462
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/092,477 Abandoned US20090304791A1 (en) | 2005-11-04 | 2006-10-20 | Solid oral forms of ebastine |
Country Status (6)
Country | Link |
---|---|
US (1) | US20090304791A1 (en) |
EP (1) | EP1944028B1 (en) |
AT (1) | ATE536873T1 (en) |
ES (2) | ES2277767B1 (en) |
PT (1) | PT1944028E (en) |
WO (1) | WO2007051877A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105326802A (en) * | 2015-09-01 | 2016-02-17 | 杭州澳医保灵药业有限公司 | Ebastine dispersible tablet and preparation method thereof |
WO2020185214A1 (en) * | 2019-03-12 | 2020-09-17 | Balto Therapeutics | Orally disintegrating tablets comprising glycopyrrolate and methods for increasing bioavailability |
CN114712322A (en) * | 2022-04-01 | 2022-07-08 | 南京联智医药科技有限公司 | Tablet of ebastine salt and preparation method thereof |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TW201113266A (en) * | 2009-09-02 | 2011-04-16 | Ziopharm Oncology Inc | Pharmaceutical formulations for indibulin |
ES2606148T3 (en) | 2011-11-01 | 2017-03-22 | Inopharm Limited | Composition of oral disintegration of antihistamine agents |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5460829A (en) * | 1991-12-03 | 1995-10-24 | Rhone-Poulenc Rorer S.A. | Pharmaceutical compositions based on ebastine or analogues thereof |
WO1999021534A1 (en) * | 1997-10-27 | 1999-05-06 | Merck Patent Gmbh | Solid state solutions and dispersions of poorly water soluble drugs |
US20030026834A1 (en) * | 2001-04-10 | 2003-02-06 | Fahkreddin Jamali | NSAIDs composition containing tartaric acid |
US20040198828A1 (en) * | 2003-01-17 | 2004-10-07 | Abelson Mark B. | Combinational use of long-acting and short-acting anti-histamines for ocular allergies |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005079752A2 (en) * | 2004-02-11 | 2005-09-01 | Rubicon Research Private Limited | Controlled release pharmaceutical compositions with improved bioavailability |
-
2005
- 2005-11-04 ES ES200502686A patent/ES2277767B1/en not_active Expired - Fee Related
-
2006
- 2006-10-20 EP EP06830886A patent/EP1944028B1/en active Active
- 2006-10-20 US US12/092,477 patent/US20090304791A1/en not_active Abandoned
- 2006-10-20 PT PT06830886T patent/PT1944028E/en unknown
- 2006-10-20 WO PCT/ES2006/000581 patent/WO2007051877A1/en active Application Filing
- 2006-10-20 ES ES06830886T patent/ES2380229T3/en active Active
- 2006-10-20 AT AT06830886T patent/ATE536873T1/en active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5460829A (en) * | 1991-12-03 | 1995-10-24 | Rhone-Poulenc Rorer S.A. | Pharmaceutical compositions based on ebastine or analogues thereof |
WO1999021534A1 (en) * | 1997-10-27 | 1999-05-06 | Merck Patent Gmbh | Solid state solutions and dispersions of poorly water soluble drugs |
US20030026834A1 (en) * | 2001-04-10 | 2003-02-06 | Fahkreddin Jamali | NSAIDs composition containing tartaric acid |
US20040198828A1 (en) * | 2003-01-17 | 2004-10-07 | Abelson Mark B. | Combinational use of long-acting and short-acting anti-histamines for ocular allergies |
Non-Patent Citations (3)
Title |
---|
SERAJUDDIN, ABU T. M.; "Solid Dispersions of Poorly Water-Soluble Drugs: Early Promises, Subsequent Problems, and Recent Breakthroughs," 1999, American Chemical Society & American pharmaceutical Association; Journal of Pharmaceutical Sciences, Vol. 88, No. 10, pp. 1058-1066. * |
SERAJUDDIN, ABUT. M.; "Solid Dispersions of Poorly Water-Soluble Drugs: Early Promises, Subsequent Problems, and Recent Breakthroughs," 1999, American Chemical Society & American pharmaceutical Association; Journal of Pharmaceutical Sciences, Vol. 88, No. 10, pp. 1058-1066. * |
Sinko, Patrick J.; "Martin's Physical Pharmacy and Pharmaceutical Sciences", 5th ed., November 2005, LIPPINCOTT WILLIAMS & WlLKINS; Chapters 10, 13, 16 and 17; pp. 231-265, 337-354, 437-467 and 469-498. * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105326802A (en) * | 2015-09-01 | 2016-02-17 | 杭州澳医保灵药业有限公司 | Ebastine dispersible tablet and preparation method thereof |
WO2020185214A1 (en) * | 2019-03-12 | 2020-09-17 | Balto Therapeutics | Orally disintegrating tablets comprising glycopyrrolate and methods for increasing bioavailability |
CN114712322A (en) * | 2022-04-01 | 2022-07-08 | 南京联智医药科技有限公司 | Tablet of ebastine salt and preparation method thereof |
Also Published As
Publication number | Publication date |
---|---|
ES2277767B1 (en) | 2008-04-01 |
EP1944028A1 (en) | 2008-07-16 |
ES2380229T3 (en) | 2012-05-09 |
EP1944028B1 (en) | 2011-12-14 |
WO2007051877A1 (en) | 2007-05-10 |
PT1944028E (en) | 2012-03-22 |
ATE536873T1 (en) | 2011-12-15 |
ES2277767A1 (en) | 2007-07-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20110014282A1 (en) | Pharmaceutical composition for poorly soluble drugs | |
JP4920798B2 (en) | Intraoral quick disintegrating tablet containing two or more kinds of particles | |
US6444225B1 (en) | Pharmaceutical composition comprising fenofibrate | |
US20140221424A1 (en) | Pharmaceutical compositions for use in the treatment of cystic fibrosis | |
EP1849830B1 (en) | Finely divided composition containing poorly water soluble substance | |
SK14572003A3 (en) | Pharmaceutical dosage form of amorphous nelfinavir mesylate | |
JP2008531509A (en) | Tablets with improved dispersibility of pharmaceutical ingredients | |
KR20070119700A (en) | Formulations containing fenofibrate and surfactant mixture | |
US20190209478A1 (en) | Tablet formulation for cgrp active compounds | |
EP1944028B1 (en) | Solid oral forms of ebastine | |
US20120214820A1 (en) | Orally disintegrating pharmaceutical dosage form containing aripiprazole | |
EP2902016A1 (en) | Febuxostat tablet | |
EP2589376B1 (en) | Oral disintegrating composition of anti-histamine agents | |
JP2006316047A (en) | Pranlukast hydrate-containing preparation having relieved bitterness | |
Mahrous et al. | Formulation and evaluation of meclizine HCl orally disintegrating tablets | |
US20040001886A1 (en) | Stabilized pharmaceutical formulations containing amlodipine maleate | |
MX2008005680A (en) | Solid oral forms of ebastine | |
US20030180354A1 (en) | Amlodipine maleate formulations | |
EP3843702B1 (en) | Immediate release fixed-dose combination of memantine and donepezil | |
JP5900702B2 (en) | Pharmaceutical composition for oral administration | |
GB2624171A (en) | An orally disintegrating tablet containing atorvastatin and process of preparing the same | |
EP4180042A1 (en) | A film coated tablet comprising micronized tofacitinib | |
WO2023232215A1 (en) | Improved pharmaceutical composition containing tadalafil and process for the preparation thereof | |
EP1808163A1 (en) | Compressed solid dosage forms with drugs of low solubility and process for making the same | |
JP2006316051A (en) | Pranlukast hydrate-containing preparation having relieved bitterness |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: SIMBEC IBERICA, S.L., SPAIN Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:ROMA MILLAN, JORDI;MESTRE CASTELL, JOSE;SUNE NEGRE, JOSE MARIA;REEL/FRAME:020899/0898;SIGNING DATES FROM 20080405 TO 20080408 |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |